Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
The invention relates to new l-furyl-3,4-dihydro-
isoquinolines of general formula
R ~ ~ ~ N
~ ~ 3
wherein Rl and R2, which may be the same or different, represent a
hydroxy or alkoxy group,
R3 represents a cyano group or a -C-Y- group,
wherein
Y repres~nts a hydroxy group, an alkoxy group or a
primary or secondary, substituted or unsubstituted, aliphatic,
cycloaliphatic, araliphatic, aromatic or heterocyclic amino
group, and the acid addition salts thereof.
The invention relates particularly to l-furyl-3,4-
dihydroisoquinolines of general formula I wherein
Rl represents a methoxy group,
R2 represents a methoxy or hydroxy group,
R3 represents a cyano group or a -C-Y- group,
O
wherein
Y represents -OH, -O-alkyl with 1 to 3 carbon atoms,
-N 0, -N(CH3)2, -N~C2H5)2'
~ f ~, ~
-NH-alkyl with l to 5 carbon atoms,
-NH-CH2-CHOH-CH3, -NH-CH2-C_ CH or a group with the partial
formula
-NH-(CH ) -R wherein
n represents the numbers l to 3 and
R represents -N(CH3~2, -OCH3, -Cl,
-N o , ~ , ~ 3
OC1-1
3 OCH3
~3
and the acid addition salts thereof.
l Furyl-3,4-dihydroiso~uinolines of general formula
113Co ~
H3CO ~ N
~ -CO-NH-R' Ia
wherein R' represents an alkyl group with l to 5 carbon atoms, a
dialkylaminoalkyl group or the group -CN, and the acid addition
salts thereof, are preferred.
Particularly preferred compounds are l-furyl-3,4-
dihydroisoquinolines of general formula Ia, wherein R' represents
an alkyl group with the partial formula -(CH2)2-CH3, -(CH2)3-CH3
s~
or -CH2-CH(CH3~2 and the acid addition salts thereof.
The new compounds may be prepared by the following
processes.
a) By cyclising an amide of furan-3,~-dicarboxylic acid of
general formula
R1 ~ C~12-C112-NH-C R3
R2
wherein Rl to R3 are as hereinbefore defined, with Lewis acids.
Suitable condensing agents include, in particular,
Lewis acids such as phosphorus trichloride, phosphorus penta-
chloride, phosphorus oxychloride, boron trifluoride and tin
tetrachloride and also strong inorganic acids such as sulphuric,
fluorosulphonic, hydrofluoric or polyphosphoric acid. They are
generally used in excess. Phosphorus oxychloride is preferred.
The cyclisation may be effected with or without a
solvent present~ All inert solvents are suitable provided that
they have a sufficient solubility for the reaction partners and
have a sufficiently high boiling point. E~amples include benzener
alkylbenzenes, chlorobenzenes, decalin, chloroform, methylene
chloride, acetonitrile and the like. In an alternative embodiment
of the process J condensing agents such as phosphorus o~ychloride
are themselves used as solvents.
There are no special conditions with regard to the
reaction temperature. The reaction according to the invention
~:~9~ ~S
may be performed within a wide temperature range, for example withheating up to the boiling point of the solvent.
b) By reacting a 3-~(3,4-dihydroisoquinolyl-(1)~-furan-4-
carboxylic acid derivative of general formula
1 ~
R ~ ~ N
~ C0 -X III
\0~
wherein Rl and R2 are as hereinbefore defined and X represents a
chlorine atom or a methoxy or ethoxy group or an imidazolide group,
with a compound of general formula
Y - H IV
wherein Y i9 as hereinbefore defined.
This reaction includes, inter alia, the conversion of
l-furyl-3,4-dihydroisoquinolines of formulae ~ and Ia into other
end products. Thus, corresponding carboxylic acid esters or
carboxylic acid amides may be converted by saponification with
strong alkalis into corresponding 3-dihydroisoquinolyl (l)-furan-
4-carboxylic acids of general formula I. With this process, it is
also possible to react acid chlorides, esters and imidazolides of
formula III with suitable amines corresponding to formula IV to
yield the compounds of formulae I and Ia.
Some of the starting compounds of formula II are new
compounds and are prepared by reacting a suitable reactive
derivative of furan-3,4-dicarboxylic acid with a primary or
511~
secondary amine directly to yield compounds of formula II or by
first preparing a monoamide derivative of furan-3,4-dicarboxylic
acid and taking this compound as such or converting it again into
a reactive form and reacting it with another amine so as to
produce a derivative corresponding to formula II.
Examples of furan-3,4-dicarboxylic acid derivatives
which are suitable for preparing the starting compounds of general
formula II include those wherein the carboxyl groups are converted
into acid halides, azides or mixed anhydrides, e.g. with an
aromatic or aliphatic carboxylic acid, alkyl carbonic acid or
dialkylphosphoric acid, or those in the form of active acid amides,
for example with imidazole, 4-substituted imidazole, dimethyl-
pyrazole, triazole or tetrazole or as active esters, e.g.
cyanomethyl, methoxymethyl, vinyl, propargyl, nitrophenyl,
methanesulfonyl or pyridylalkyl esters or as esters with dimethyl-
hydroxylamine, 1 hydroxysuccinimide, l-hydroxybenzotriazole,
dicyclohexylurea, etc. Monoethyl furan-3,4-dicarboxylate chloride
is preferred.
The amide formation i5 generally effected in a solvent
such as dioxan, acetonitrile, tetrahydrofuran, pyridine or any
other organic solvent which does not harm the reaction, optionally
in the presence of an organic or inorganic base as the acid binding
agent. These solvents may also be used in the form of a mixture.
Howeverl it is also possible to use an excess of amine as the
solvent.
The reaction temperature is not critical and the reaction
is generally carried out with cooling, at ambient temperature or
with heating.
s~s
Starting compounds of formula III may be prepared from
the corresponding 3 ~(3,4-dihydroisoquinolyl~ furan-4-carboxy-
lic acids.
The l-furyl-3,~-dihydroisoquinolines of general formula
I according to the invention are bases and may be converted in the
usual way lnto any desired physiologically acceptable acid addition
salts formed with inorganic or organic acids. Acids suitable for
salt formation include, for example, hydrochloric, hydrobromic,
hydroiodic, hydrofluoric, sulphuric, phosphoric, nitric, acetic,
propionic, butyric, caproic, valeric, oxalic, malonic, succinic,
maleic, fumaric, lactic, tartaric, citric, benzoic, p-
hydroxybenzoic, p-aminoben20ic, phthalic, cinnamic, salicylic or
ascorbic acid, 8-chlorotheophylline, methanesulphonic acid and the
like.
Tests on animals have shown that the new l-furyl-3,4-
dihydroisoquinolines of general formula I have valuable therapeutic
properties, both as bases and also in the form of their salts.
In particular, they improve blood circulation in the tissues and
the supply of oxygen to the tissues, particularly in the central
nervous system. They also have a contractility-increasing effect
and they influence blood pressure. For the indication given, the
compounds constitute a new class of substances; they are therefore
particularly useful in cases in which the conventional pharmaceu-
tical compositions already on the market are unsuccessful. More-
over, the compounds described are highly versatile intermediate
products.
5 ~5
The toxicities are generally small, as has been demon-
strated by toxicity tests in mice, by intravenous and oral adminis-
tration.
In view of these effects, the compounds of general
formula I may be used as active substances for pharmaceutical
compositions for the treatment of circulatory and coronary dis-
orders. The active substance according to the invention may be
administered by the enteral or parenteral route. The dosage fGr
oral administration is between 0.05 and 50 mg per kg and the dos-
age for intravenous administration is between 0~01 and 10 mg
preferably from 1 to 5 mg/kg.
The new l-furyl-3,4-dihydroisoquinolines of general
formula I and the acid addition salts thereof may also be combined
with active substances of other Xinds. Suitable galenic prepara-
tions include, for example, tablets, capsules, suppositories,
solutions or powders; they may be prepared using the conventional
galenic excipients, carriers, disintegrants or lubricants or sub-
stances for obtaining delayed release.
The following examples illustrate the invention without
restricting it.
Intermediate products
1. Monoeth~l furan-3,4-dicarboxylate
A solution of 235 g of diethyl furan-3,4-dicarboxylate
and 62.1 g of potassium hydroxide in 800 ml of 60~ ethanol was
stirred at ambient temperature for 2 hours and then the excess
solvent was distilled off in vacuo. The mixture was acidified b~
J5~5
carefully adding a KHS04 solution dropwise thereto, with stirring,
and the half ester was extracted with CH2Cl2 and crystallised
from ethyl acetate/petroleum ether.
Yield: 169.3 g (= 83% of theory).
2. Monoethyl furan-3,4-dicarboxylate chloride
183 g of monoethyl furan-3,4-dicarboxylate were refluxed
together with ll9 g of thionyl chloride in a water bath for 90
minutes with stirring. Excess thionyl chloride was drawn off in
vacuo and the residue was distilled under reduced pressure (147-
14~/16 mm~Ig), and 183.4 g (91% of theory) of half ester chloride
were obtained.
3. Ethyl 3-~(3,4-dimethoxyphenyl)-2-ethylaminocarbonylJ-
furan-4-carboxylate
295 g of monoethyl furan-3,4-dicarboxylate chloride in
500 ml of absolute tetrahydrofuran were added dropwise, at ambient
temperature, with stirring, to a cooled mixture of 263 g of 2-
(3,4-dimethoxyphenyl)- ethylamine, 171 g of triethylamine and 500
ml of absolute tetrahydrofuran. After the reaction had ended, the
precipitated triethylammonium chloride was suction filtered, the
filtrate was concentrated by evaporation and the solid residue was
distributed between water and methylene chloride~ The organic
phase was dried over Na2S04. After the solvent had been distilled
off, the product was recrystallised from ethyl acetate.
Yield: 459 g (=91% of theory); melting point: 90-92C.
4. 3-~(3,4-Dimethoxyphenyl)-2-ethylaminocarbonyl~-furan-4-
carboxylic acid
~9~5'1~5
31.9 g of ethyl 3-~(3,4-dimethoxyphenyl)-2-e-thylamino-
carbonyl~-furan-4-carboxylate were dissolved in 150 ml of methanol
and stirred with 150 ml of lN sodium hydroxide solution for 45
minutes at 50C. Then the mixture was neutralised, excess solvent
was distilled off, the half-amide was extracted with methylene
chloride and crystallised from ethyl acetate/petroleum ether.
Yield: 25.5 g (= 87.3% of theory); melting point: 188-189 CO
5. 3-~(3,4-Dimethoxyphenyl)-2 ethylaminocarbony ~-furan-4-
carboxylic acid-n-propylamide
Method A
A solution of 30 g of 3-~(3 t 4-dimethoxyphenyl)-2-ethyl-
aminocarbonyl~-furan-4-carboxylic acid and 16.2 g of N,N'-carbonyl-
diimidazole in 150 ml of absolute tetrahydrofuran was stirred for
l hour at ambient temperature, whilst moisture was excluded. Then
7 ml of n-propylamine were added and the mixture was stirred for
a further 4 hours at ambient temperature. After the reaction had
ended, the solvent was eliminated in vacuo, the residue was dis-
solved in methylene chloride and washed successively with dilute
hydrochloric acid and water. The organic phase was dried over
Na2SO4, the solvent was removed and the residue was crystallised
from ethyl acetate.
Yield: 2904g (=87~ of theory).
Method B
63 g of ethyl [(3,4-dimethoxyphenyl)-2-ethylaminocarbonyl~
-furan-4-carboxylate and 120 ml of n-propy~amine were heated to
120 in the autoclave for 24 hours. The reaction mixture was
6~S~S
mixed with 300 ml of methanol and treated with active charcoal at
boiling temperature. After cooling the mixture was suction
filtered and concentrated by evaporation and the residue was
crystallised from ethyl acetate/petroleum ether. If necessary,
purification is first effected over a silica gel column (CH2C12:
MeOH = 100:1 ~ 100:2).
Yield: 51 g (=78% of theory).
Examples of preparation
Example 1
Ethyl 3-~3,4-dihydro-6,7-dlmethoxy-isoquinolyl-(1)~-furan-4-
carboxylate
50 g of 3-carbethoxy-furan-4-carboxylic acld-~2-(3,4-
dimethoxyphenyl)-ethylJ-amide are dissolved ln 120 ml of aceto-
nitrile and 18 ml of phosphorus oxychloride are added. r~he reac-
tion mixture is kept at reflux temperature for about 2 hours.
Then concentration is effected by evaporation, the residue is
taken up in 200 ml of methylene chloride and made alkaline by
stirring into an ice-cold water/potassium carbonate solution.
After working up in the usual way - extracting with methylene
chloride, drying the organic phase over Na2SO4, removing the sol-
vent - the product is purified over a silica gel column (CH2C12:
MeOH = 100:1 ~ 100:2).
Yield: 37.5 g (=79% of theory); melting point: 151~153C.
Example 2
3-~ 3,4-Dihydro-6,7~dimethoxy-isoquinolyl-~(1)7-furan-4-carboxylic
acid hydrochloride
-- 10 --
~:~9~)5'~
Eor hydrolysis, 15 g of ethyl 3~ 3,4-dihydro-6,7-di-
methoxyisoquinolyl~ furan-4-carboxylate were dissolved in 50
ml of ethanol and at 50C 45 ml of potassium hydroxide solution
were added. After about 60 minutes, the mixture was neutralised,
the solvent was distilled off, the dry residue was -taken up in
ethanol, alcoholic hydrochloric acid was added and the resulting
mixture was suction filtered. The filtrate was concentrated by
evaporation and brought to crystallisation with acetone. After
recrystallisation from methanol/ether, if necessary with the aid
of active charcoal, 13.6 g (= 88.4~ of theory) of pure product
remained. Melting point: 212-214 C.
Example 3
3-C3,4-Dihydro-6l7-dimethoxy-isoquinolyl~ -furan-4-carboxylic
acid-n-propylamide
Method A
40 g of 3-(n-propylaminocarbonyl)-furan-4-carboxylic
acid-~2-(3,4-dimethoxyphenyl)-ethyl~amide were dissolved in 400
ml of acetonitrile and refluxed with 25 ml of phosphorus oxychlor-
ide for about 2 hours. The mixture was then concentrated by
evaporationl the residue was taken up in 200 ml of methylene
chloride and made alkaline by stirring it into an ice-cold water/
potassium carbonate solution. Working up was effected as described
in Example 1 and purification was effected over a silica gel
column (CH2C12: MeOH = 100~ 100:2).
In order to prepare the hydrochloride the base was dis-
solved in as little ethanol as possible and then ethanol hydro-
s
chloric acid was added. The hydrochloride was crystallised out by
adding absolute ether dropwise thereto.
Yield: 24.1 g (= 57% of theory); melting point: 199-205C (decom-
position).
Method s
30.1 g of 3-~3,4-dihydro-6,7-dimethoxy-isoquinolyl~
furan-4-carboxylic acid were refluxed in 60 ml of thionyl chloride
for 40 minutes. Then the excess thionyl chloride was removed in
vacuo and the mixture was added in batches, with stirring, to an
ice-cooled solution of 13 g of n-propylamine in 200 ml of absolute
tetrahydrofuran. After about 1 hour, the mixture was worked up
in -the usual way, the reaction product was purified over a column
of silica gel and crystallised in the form of the hydrochloride
from MeOH/ether.
Yield: 16.8 g (= 44.5~ of theory); melting point: 204-205C.
Method C
33.8 g of 3-~3,4-dihydro 6,7-dimethoxy-isoquinolyl-(l)~-
furan-4-carboxylic acid and 17.2 g of N,N'-carbonyl-diimidazole
were dissolved in 150 ml of absolute tetrahydrofuran at the reflux
temperature and after l hour 7 ml of n-propylamine were added.
The mixture was stirred overnight at ambient temperature, then
the solvent was distilled off in vacuo and the residue was distri-
-
buted between methylene chloride and water. The organic phase
was dried and concentrated by evaporation; the residue was puri-
fied over a silica gel column and crystallised in the form of the
hydrochloride from MeOH/ether.
Yield: 7.5 g (- 15% of theory); melting point: 203-204C.
- 12 -
59~i
Example 4
3-~3,4-Dihydro-6,7-dimethoxy-isoquinolyl~ -furan-4-carboxylic
acid nitrile
10 g of 3-~2-(3,4-dimethoxyphenyl)-ethylaminocarbonyl~-
furan-4-carboxylic acid amide were refluxed with 30 ml of phos-
phorus oxychloride in 50 ml of acetonitrile for 1.5 hours as in
Example 1. After the usual working up and purification over a
column of silica gel, the hydrochloride was crystallised from
methanol/ether.
YiPld: 7.8 y (= 77% of theory); melting point: 204-207C.
The following compounds of general formula I were pre-
pared analogously to the Examples above:
5 ~5
Example Rl R2 3 ~ M.p. ~ C) Salt Form
5. CH30 OH COOC2H5 173-175 Base
6. CH30 CH30 CONHCH3 246 HCl
7. CH30 CH30 CON(CH3)2 167-168 (D)
8. CH30 CH30 CONHCH2CH3 212-215 (D) HC1
9. CH30 CH30 CON(CH2CH3)2 203-205 (D) HCl
10. CH30 CH30 CONH(CH2)3CH3 216 (D) HC1
11. CH30 CH30 CONH(CH2)4CH3 215-218 (D) HCl
12. C~I30 CH30 CONHCH2CH(CH3)2 195-200 (D) HC1
13. CH30 CH30 CONHCH2CH2CH(CH3)2 222-225 (D) E~Cl
14. CH30 CH30 CONH-CH2 C_CH 244-245 (D) HCl
15. CH30 CH30 CONH(CH2)2N(CH3)2 162-165 HCl
16. CH30 CH30 CONH(CH2)3N(CH3)2 116-125 (D) HC1
17. CH30 CH30 CONH-CH2CH20CH3 216-218 (D) HCl
18. CH30 CH30 CONH-CH2-CH2-CH2C1 233-237 (D) HC1
19. CH30 CH30 CO-NH--CH2-CH(OH)-cH3 218-224 (D) HCl
20. CH30 CH30 CO-N~_~O 141-144 HCl
21. CH30 CH30 CO-NH-CH2CH2-N o 183-185 HC1
22. CH30 CH30 CONH-CH2CH2- ~ 221-222 HCl
3 OCH3
23. CH30 CH30 CO-NH-CH2-CH2- ~ 194-198 HCl
OCH3
24. CH30 CH30 CO-NH-CH2-CH2- ~ OCH3 186-192 HC1
~ OCH3
25. CH30 CH30 CO-NH-CH2/~ 231-234 HCl
- 14 -
5~i
Examples of formulations
Example A: Coated tablets
Actlve substance according to invention 5 mg
Lactose 65 mg
Corn starch 130 mg
Sec. calcium phosphate 40 mg
Soluble starch 3 mg
Magnesium stearate ~ 3 mg
Colloidal silicic acid 4 mg
Total 250 mg
Preparation:
The active substance is mixed with some of the excipients,
intensively kneaded with an aqueous solution of the soluble starch
and granulated in the usual way by means of a screen. The
granulate is mixed with the remaining excipients and compressed to
form tablet cores weighing 250 mg which are coated in the usual
way using sugar, talc and gum arabic.
Example B: Ampoules
-
Active substance according to invention 1.0 mg
Sodium chloride 18.0 mg
Distilled water ad 2.0 ml
Preparation:
Active substance and sodium chloride are dissolved in
water and transferred into glass ampoules under nitrogen.
Example C: Drops
Active substance according to invention 0.02 g
Methyl p-hydroxybenzoate 0.07 g
Propyl p-hydroxybenzoate 0.03 g
Dimineralised water ad 100 ml
- 16 -
